Voltage dependent calcium channels (VDCCs) are multimeric proteins that reside in the surface membranes of cells. When activated they allow calcium ions to move into the cell and thus contribute to the regulation of a wide range of cellular functions and physiological processes. For instance, the activation of voltage dependent calcium channels contributes to the electrical excitability and normal function of the brain, the release of neurotransmitters, the transmission of pain signals, skeletal and cardiac muscle contraction, the regulation of gene expression, cell motility, division, and development. Agents with the ability to alter calcium channel function have the potential to modify such important cellular and physiological processes.
Structurally, VDCCs are heteromeric proteins consisting of a pore-forming α1 subunit and, potentially, as many as three auxiliary subunits: α2δ, β and γ. The α1 subunit contains the permeation pathway for calcium ions and the voltage sensing regions that control channel gating. Thus they determine to a great extent the major characteristics of the calcium current carried by the different calcium channel subtypes. The auxiliary subunits act, in a sense, as regulators of VDCC current. For instance, when co-expressed with an α1 subunit the auxiliary subunits α2δ and β act as positive regulators of calcium channel function. They enhance trafficking of the channel complex to the surface membrane thus increasing current density. They also alter the biophysical properties of the channel in ways that enhance activation. Two of the eight known γ subunits (γ1 and γ6) seem to function primarily as negative regulators of calcium current. When co-expressed with calcium channel α1 subunits, γ1 and γ6 decrease calcium current density.
The unique ability of the γ6 subunit to decrease calcium current in cells forms the basis for this invention. To address the need for new agents capable of regulating calcium transport, we report new compositions and methods for control of calcium channel function.